A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection

Blume, Cornelia; Jackson, Claire; Spalluto, Cosma; Legebeke, Jelmer; Nazlamova, Liliya; Conforti, Franco; Perotin, Jeanne-Marie; Frank, Martin; Butler, J. A. V.; Crispin, Max; Coles, Jonathan A.; Thompson, James; Ridley, Robert; Dean, Lareb S. N.; Loxham, Matthew; Reikine, Stephanie; Azim, Adnan; Tariq, Kamran; Johnston, D.; Skipp, Paul; Djukanović, Ratko; Baralle, Diana; McCormick, Christopher J.; Davies, Donna E.; Lucas, Jane S.; Wheway, Gabrielle; Mennella, Vito

doi:10.1038/s41588-020-00759-x

Cited by 141 publications

(159 citation statements)

References 73 publications

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“…2a). Immunoblotting confirmed detection of the correct molecular mass of ~110/120 kDa and recently reported 12,49 short 50-kDa isoforms of endogenous ACE2 in both cell types (Extended Data Fig. 2b).…”

Section: Ace2 and Tmprss2 Expression In Endocrine Cells And A Ductal Subpopulationsupporting

confidence: 80%

“…Fignani et al 12 provide a comprehensive analysis on ACE2 expression in β-cells, including mass-spectrometry-based detection. Briefly, this study showed that the short ACE2 isoform is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin-producing β-cells 12,49 . It is interesting also that Kusmartseva et al reported detectable mRNA levels of ACE2 in a proportion of endocrine cells 13 .…”

Section: Discussionmentioning

confidence: 99%

“…These different experimental outcomes might be attributed to intra-and interindividual variations in the investigated donor tissue, or utilization of antibodies that have various affinities to the respective isoforms 12,13,34,36 . In the present study, we used established antibodies in our immunohistochemistry analysis that detect the short and long isoforms and, in addition, performed an extensive in-house characterization of these antibodies and the applied methodology 12,36,49 . Fignani et al 12 provide a comprehensive analysis on ACE2 expression in β-cells, including mass-spectrometry-based detection.…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

et al. 2021

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Initially, the pandemic COVID-19, caused by SARS-CoV-2, was considered to be an exclusive lung disease, eventually leading to serious respiratory symptoms 1 . In the meantime, accumulating experimental and clinical studies have suggested that SARS-CoV-2 may also cause lesions in the kidneys, heart, brain, and gastrointestinal and endocrine organs [2][3][4][5][6][7] . SARS-CoV-2 tropism towards distinct tissues is governed by cellular factors expressed on target cells such as the viral entry receptor angiotensin-converting enzyme 2 (ACE2) 8 and the transmembrane serine protease 2 (TMPRSS2) 8 . ACE2 messenger RNA 9-13 and protein 12-14 expression within the islets of Langerhans has been reported, but not yet been shown, to allow SARS-CoV-2 entry 9,12,15 . Diabetes mellitus presents Janus like in 16 ): first, pre-existing diabetes is a highly prevalent comorbidity observed in 11-22% of patients and as such increases the risk of a severe disease, requiring more intense interventions and increasing mortality [17][18][19][20][21][22] . Second, SARS-CoV-2 infection seems to affect the exocrine pancreas, manifesting as pancreatitis in 32.5% of critically ill patients 23 , and pancreatic enlargement and abnormal amylase or lipase levels in 7.5-17% of patients 9,22 . Third, metabolic dysregulation has been observed in patients with COVID-19 as:(1) increased hyperglycaemia in patients with type 2 diabetes 24 ; (2) ketoacidosis in 2-6.4% of diabetic and non-diabetic patients 18,25 ; and (3), in case studies reporting ketoacidosis on SARS-CoV-2 infection, accompanied by (4) new-onset type 1 diabetes mellitus (T1DM) in the absence of autoantibodies [26][27][28] . In a cohort study of patients with diabetes, hyperglycaemia was reported in more than 50% of all cases, and almost a third experienced diabetic ketoacidosis 29 . Finally, a multicentre study found an 80% increase of new-onset T1DM in children during the COVID-19 pandemic 30 . In accordance, a recent meta-analysis summarizes that severe SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

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Section: Ace2 and Tmprss2 Expression In Endocrine Cells And A Ductal Subpopulationsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

et al. 2021

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“…Further, the absence of a transcriptional response to secreted interferon cannot be explained by a lack of either interferon alpha receptor ( IFNAR1, IFNAR2 ) or interferon gamma receptor ( IFNGR1, IFNGR2 ) expression. Previous work has identified ACE2 , the host receptor for SARS-CoV-2, as among the interferon-induced genes in nasal epithelial cells, with uncertain significance for SARS-CoV-2 infection 29,81–83 . Indeed, we find modest upregulation of this gene among cells from COVID-19 participants compared to healthy controls.…”

Section: Resultsmentioning

confidence: 99%

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Ziegler

Miao

Owings

et al. 2021

Preprint

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Infection with SARS-CoV-2, the virus that causes COVID-19, can lead to severe lower respiratory illness including pneumonia and acute respiratory distress syndrome, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood. Here, we present nasopharyngeal samples from a cohort of 35 individuals with COVID-19, representing a wide spectrum of disease states from ambulatory to critically ill, as well as 23 healthy and intubated patients without COVID-19. Using standard nasopharyngeal swabs, we collected viable cells and performed single-cell RNA-sequencing (scRNA-seq), simultaneously profiling both host and viral RNA. We find that following infection with SARS-CoV-2, the upper respiratory epithelium undergoes massive reorganization: secretory cells diversify and expand, and mature epithelial cells are preferentially lost. Further, we observe evidence for deuterosomal cell and immature ciliated cell expansion, potentially representing active repopulation of lost ciliated cells through coupled secretory cell differentiation. Epithelial cells from participants with mild/moderate COVID-19 show extensive induction of genes associated with anti-viral and type I interferon responses. In contrast, cells from participants with severe lower respiratory symptoms appear globally muted in their anti-viral capacity, despite substantially higher local inflammatory myeloid populations and equivalent nasal viral loads. This suggests an essential role for intrinsic, local epithelial immunity in curbing and constraining viral-induced pathology. Using a custom computational pipeline, we characterized cell-associated SARS-CoV-2 RNA and identified rare cells with RNA intermediates strongly suggestive of active replication. Both within and across individuals, we find remarkable diversity and heterogeneity among SARS-CoV-2 RNA+ host cells, including developing/immature and interferon-responsive ciliated cells, KRT13+ "hillock"-like cells, and unique subsets of secretory, goblet, and squamous cells. Finally, SARS-CoV-2 RNA+ cells, as compared to uninfected bystanders, are enriched for genes involved in susceptibility (e.g., CTSL, TMPRSS2) or response (e.g., MX1, IFITM3, EIF2AK2) to infection. Together, this work defines both protective and detrimental host responses to SARS-CoV-2, determines the direct viral targets of infection, and suggests that failed anti-viral epithelial immunity in the nasal mucosa may underlie the progression to severe COVID-19.

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“…Southeast Asians have greater body fat than Europeans and North Americans for the same BMI, meaning Southeast Asians cannot be treated as obese despite their larger visceral fat amounts [27]. It has been shown that the SARS-CoV-2 virus uses angiotensin-converting enzyme 2 (ACE2) as a gateway into the body [28][29][30]. ACE2 is a cell-surface exoenzyme that converts angiotensin II (Ang II) into vasodilatory angiotensin 1-7 (Ang 1-7).…”

Section: The Obesity Paradox Visceral Fat and Covid-19 Outcomesmentioning

confidence: 99%

The Obesity Paradox Predicts the Second Wave of COVID-19 to Be Severe in Western Countries

Krams

Jõers

Luoto

et al. 2021

IJERPH

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While COVID-19 infection and mortality rates are soaring in Western countries, Southeast Asian countries have successfully avoided the second wave of the SARS-CoV-2 pandemic despite high population density. We provide a biochemical hypothesis for the connection between low COVID-19 incidence, mortality rates, and high visceral adiposity in Southeast Asian populations. The SARS-CoV-2 virus uses angiotensin-converting enzyme 2 (ACE2) as a gateway into the human body. Although the highest expression levels of ACE2 are found in people’s visceral adipose tissue in Southeast Asia, this does not necessarily make them vulnerable to COVID-19. Hypothetically, high levels of visceral adiposity cause systemic inflammation, thus decreasing the ACE2 amount on the surface of both visceral adipocytes and alveolar epithelial type 2 cells in the lungs. Extra weight gained during the pandemic is expected to increase visceral adipose tissue in Southeast Asians, further decreasing the ACE2 pool. In contrast, weight gain can increase local inflammation in fat depots in Western people, leading to worse COVID-related outcomes. Because of the biological mechanisms associated with fat accumulation, inflammation, and their differential expression in Southeast Asian and Western populations, the second wave of the pandemic may be more severe in Western countries, while Southeast Asians may benefit from their higher visceral fat depots.

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A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection

Cited by 141 publications

References 73 publications

SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

The Obesity Paradox Predicts the Second Wave of COVID-19 to Be Severe in Western Countries

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